Project Summary Sj?gren?s syndrome (SS) is a prevalent and systemic autoimmune disorder that strikes millions of people in the US alone and results in severe dryness of mouth and eyes as major clinical symptoms. Excessive production of type I interferons (IFNs) has been characterized as a key pathogenic factor in SS. Our long-term goal is to understand the precise role of major type I IFN-producing cell types in the pathogenesis of SS and provide critical knowledge and basis for the development of effective cell-targeted interventions against this disease. As the most potent producers of type I IFNs, plasmacytoid dendritic cells (pDCs) are critically involved in the induction of multiple autoimmune diseases. However, there is a fundamental gap in understanding the function of pDCs in the pathogenesis of SS. The objective of this proposed project is to define the precise in vivo role of pDCs in SS development. Previous studies on SS patients have demonstrated the appearance of pDCs and activated type I IFN pathways in the disease target salivary glands, and the degree of tissue inflammation and secretory dysfunction closely correlates with type I IFN activity. Consistent with this, our preliminary studies confirmed the pathogenic role of type I IFN pathways in SS using non-obese diabetic (NOD) mice, a well-defined spontaneous model of SS, and showed the presence of pDCs in the submandibular glands (SMGs) of NOD mice, but not in those of control BALB/c mice. The number of pDCs and the total mRNA amount of IRF-1 and IRF-7, two type I IFN-responsive genes in the SMGs of NOD mice were increased accompanying SS development. Moreover, our findings indicated pDCs as the major cell sources of type I IFNs in the SMGs and the potential pathogenic role of pDCs in SS. Additionally, the appearance of pDCs in the SMGs was also detected in a salivary gland antigen-induced mouse model of SS accompanied with local upregulation of IRF-1 and IRF-7. Based on these lines of evidence, we hypothesize that pDCs function as crucial disease-promoting factors in the development of SS, a type I IFN-dependent autoimmune disease. This hypothesis will be tested by the following strategies: 1) Determine whether depletion of pDCs will impede the development of SS and inhibit the activities of type I IFN pathways and other pathogenic immune cells in the SMGs in both mouse models of SS. 2) Assess whether adoptive transfer of activated pDCs will accelerate the development of SS and enhance the activities of type I IFN pathways and other pathogenic immune cells in the SMGs in both SS mouse models. The proposed research is of great significance, because it is expected to fill the gap in understanding pDC-mediated pathogenesis of SS. We anticipate that this study could offer promising pDC-targeted interventions to combat SS.